Propargylamine as an anti-depressant



United States Patent 3,297,527 PROPARGYLAMINE AS AN ANTI-DEPRESSANT Edward F. Elslager, Ann Arbor, Mich, assignor t0 Parke, Davis & Company, Detroit, Mich, a corporation of Michigan No Drawing. Filed Oct. 9, 1963, Ser. No. 314,861 1 Ciaim. (Cl. 16765) The present invention relates to pharmaceutical compositions useful in the treatment of depression and car diovascular ailments such as hypertension and to methods for treatment embodying the use of these compositions.

More particularly, the present invention relates to pharmaceutical compositions containing as an active ingredient propargylamine in free base or physiologically acceptable inorganic and organic acid addition salt form. As examples of some of the many physiologically acceptable salts contemplated, there may be mentioned the hydrochloride, hydrobromide, hydroiodide, nitrate, bisulfite, bisulfate, hemisulfate, perchlorate, acetate, palmitate, stearate, hemipamoate, picrate, decanesulfonate, 4-chloro-2 (S-chlorosalicyl) phenoxide,'hydroxynaphthoate, dodecylsulfate, cyclohexanesulfamate, phenolphthalein,trichorophenoxide, 2,2 thiobis(4,6-dichlorophenoxide), deoxycholate, 7-chloro 4-hydroxy-3-quinolinecarboxylate, dihydroxyisonicotinate, bromonaphthoxide, hemiadipate p toluene sulfonate, hemi (5,5- thiodisalicylate), 3,5-dichlorosalicylate, taurocholate, dioctylsulfosuccinate and 2,6-di-iodo 4 nitrophenoxide. The acid addition salts are conveniently formed from the free base by mixing the free base with at least an equivalent amount of the acid in a solvent in which the salt is insoluble, particularly after chilling, thereby permitting recovery of the desired salt as a solid phase. Whereas both the free base and salt forms are useful for the purposes of the invention, the salts are generally preferred in those cases where increased stability and water solubility are desirable. In general, the choice of anion is not critical since the above-mentioned cation constitutes the active moiety. The selection and provision of salt-s for the purposes of the invention will be understood by those skilled in the art in accordance with methods and considerations which will be known to them. Preferred compositions of the invention are those which include as an active ingredient propargylamine hydrochloride. The invention also contemplates compositions Which include not only propargylamine in free base or acid addition salt form but also a therapeutically effective amount of a diuretic agent such as hydrochlorthiazide, chlorthiazide, hydrofiumethiazide, benzhydroflumethiazide and the like.

The invention is based on the unexpected finding that propargylamine and its acid addition salts at well tolerated dosage cause a striking elevation in tissue norepinephrine levels and also possess significant antireserpine activity. For example, propargylamine hydrochloride administered to rats at a dose of 40 mg./kg. daily for four days by the intraperitoneal route elevates the norepinephrine level beyond control levels by as much as 130% in the heart and 185% in the brain, in accordance with the assayprocedure described in Acta Phys. Scand, vol. 118, Sup. 33, page 45 (1955).

According to the present invention, pharmaceutical compositions are produced by formulating the free base propargylamine or physiologically acceptable acid addition salts thereof in dosage unit form. Such compositions are constituted with pharmaceutical carriers or diluents. In view of the oral activity of propargylamine and its salts, dosage unit forms for oral administration are particularly suitable, such as tablets, powders, capsules, solutions and suspensions in which the propargyl- Ice amine compound is incorporated with a carrier or diluent. Solid carriers and diluents include sugars such as lactose and sucrose; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose and cellulose acetate phthalate; gelatin (including hard and soft shell capsules); talc, corn starch, stearic acid and magnesium stearate. Liquid carriers and diluents suitable for use include vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyethylene glycol; propylene glycol; glycerine; sorbitol, ethanol; and water. Suitable preservatives and flavoring agents can also be incorporated in such compositions. In the production of dosage forms such as tablets, an enteric coating or sugar coating can be applied to make the medicament more palatable. If administration by the parenteral route is desired, the composition can be formulated in ampoule form as a suspension or solution in a liquid diluent. Other therapeutic agents can also be incorporated with the compositions.

The concentration of the propargylamine compound (reckoned as free base content) in the compositions can be varied within wide limits but, for practical purposes, is preferably at least 5% by weight. As will be appreciated, the upper concentration limit is not critical.

It will be understood that the dosage regiment for the compositions of the invention will vary, depending on various factors. In general, however, the daily oral dosage range, calculated as propargylamine free base content, is about 10 to 250 mg. per kilogram of body weight, in single or divided doses; and the dosage is continued until the condition under treatment is relieved.

In the preparation of dosage unit forms such as tablets or capsules, the quantity of medicament furnished by each dosage unit form is selected such that the proper dose can be reached by administering either one or a reasonable number of the dosage units. For convenience of manufacture and ease of administration, it is preferable that such dosage forms contain at least 2.5 mg. or more up to mg. of the propargylamine compound (calculated as free base) per unit.

The invention is illustrated by the following examples showing various suitable dosage forms and the preparation thereof.

EXAMPLE 1 A solution of salicyclic acid (1.38 parts by Weight) in ether (15 parts by volume) is added with stirring to a solution of propargylamine (0.55 part by weight) in ether (10 parts by volume). The resulting crystalline product, propargylamine salicylate, is collected by filtration, washed with ether and recrystallized from dioxaneether; M.P. -146 C. The cor-responding propargylamine hydrochloride is obtained by treating the ethereal propargylamine solution with excess hydrogen chloride and isolating the resulting crystalline hydrochloride salt, in the same manner, M.P. afterrecrystallization from methanol-ether 178181 C.

Likewise, other propargylamine salts, as follows, are obtained by mixing an ether or acetone solution of one equivalent of the respective acid (one-half equivalent for dibasic acids) with the propargylamine solution and isolating the resulting crystalline salt product:

Propargylamine sulfate; M.P. 162166 C., from methanol-ether.

Propargylamine 2,2 thiobis (4,6-dichlorophenoxide);

M.P. 171l77 C., from Z-propanol.

Propargylarnine acetate; M.P. 86-92 C.

Propargylamine 3-hydroxy-2-naphthoate; M.P. 159

C., from Z-propanol.

Propargylarnine p-toluenesulfonate; M.P. l56-l58 C.,

from acetone.

3 EXAMPLE 2 Formula for emulsion (100 ml.)

Propargylamine mg 100 Isopropyl palmitate ml 20 Polyethylene sorbitan 60 (Tween 60) "g" 3 Sorbitan 80 (Span 80) -g 2 Sugar, U.S.P. g 10 Sodium benzoate g 0.5 Flavors, q.s.

Color, q.s.

Distilled water, q.s. ad. 100 m1.

MANUFACTURING INSTRUCTIONS Dissolve the propargylamine in the isopropy-l palmitate by heating. Add the Span 80 and Tween, heating to 65 C., so that all are melted together. Dissolve the sugar and sodium benzoate in water and heat to 67-70 C. Add the water phase to the oil phase with thorough agitation. Allow the emulsion to cool and then add the Distilled water, q.s. ad. 100 ml.

MANUFACTURING INSTRUCTIONS (l) Dissolve the propargylamine hydrochloride in 60 ml. of water with stirring. Add the sodium benzoate, sodium citrate, citric acid, sugar, glycerin, dye and flavor.

(2) Adjust the volume to 100 ml. with distilled water. Filter the solution.

EXAMPLE 4 Formula for hard shell capsules G. Propargylamine hydrochloride 2.5 Milk sugar powder, U.S.P.- 175 No. 4 opaque capsule, gelatin hard shell MANUFACTURING INSTRUCTIONS 1) Pass the propargylamine hydrochloride and milk sugar through a No. 30 mesh screen. Blend thoroughly in a twin shell blender.

(2) Fill the powder blend into No. 4 opaque hard shell gelatin capsules using a capsule filling machine. Yield, approximately 1000 capsules each containing 2.5 mg. of propargylamine hydrochloride. Instead of propargy-lamine hydrochloride in the above formulation, one can use an equal amount of other acid addition salts or propargylamine. For example, one can use any of the salts set forth in Example 1.

EXAMPLE Formula for 5 mg. tablets G. Propargylamine hydrochloride 5 Sugar with 3% starch, powdered 165 Milk sugar, U.S.P., powder 165 Solution A (acacia solution), q.s. Corn starch, sifted 30 Talc, sifted Magnesium stearate, U.S.P. 3

MANUFACTURING INSTRUCTIONS (1) Blend the propargylamine hydrochloride, powdered sugarpand milk sugar in a twin shell blender.

(2) Wet granulate the powder blend with solution A. Finish granulating with distilled water, if necessary.

(3) Screen the wet granulation through a No. 6 stainless steel screen.

(4) Dry overnight at 130 F.

(5) Reduce the dried granulation through a No. 14 stainless steel screen.

(6) Blend in the corn starch, talc and magnesium stearate.

(7) Compress the blend on a rotary tableting machine using concave punches. Yield, approximately 1000 tablets each containing 5 mg. of propargyla-mine hydrochloride.

Other salts of propargylamine such as those of Example 1 can be substituted for the hydrochloride in this formulation. An alternative materials list for making 1000-lot capsules by this procedure, each containing 50 mg. of propargylamine p-toluenesulfonate is the follow- G. Propargylamine p-toluenesulfonate 50 Dibasic calcium phosphate Milk sugar, U.S.P., powder 140 10% w./w. polyvinylpyrrolidone solution, q.s. Corn starch, sifted 40 Talc, sifted 10 Magnesium stearate, U.S.P. 3

EXAMPLE 6 Formula for solution (100 ml.)

Propargylamine sulfate mg 200 Sugar, medium granular cane -g 20 Sodium citrate, U.S.P. g 0.25 Sodium benzoate, U.S.P. g 0.5 Sulfuric acid, q.s. to pH 5.0 Glycerin, U.S.P. ml 5 ED. & C. Red No. 4 m-g 0.003 Cherry flavor ml 0.5

Distilled Water, q.s. ad. 100 ml.

MANUFACTURING INSTRUCTIONS (l) Dissolve the propargylamine sulfate in 60 ml. of Water with stirring. Add the sodium benzoate, sodium citrate, sugar, glycerin, dye and flavor.

(2) Adjust the pH to 5.0 with sulfuric acid solution.

(3) Bring the volume up to 100 ml. with distilled water. Filter the product.

EXAMPLE 7 Formula for supserzsion (100 ml.)

G. Propargyl'amine 3-hydroxy-2-nahpthoate 1.0 Polyethylene sorbitan 60 (Tween 60) 0.1 Sodium saccharin 0.02 Cyclamate sodium (sodium Sucaryl) 0.03 Sugar, med. granular 10 Methylcellulose (Methocel, U.S.P.) 0.2 Flavor, q.s. Dye, q.s. Sodium benzoate 0.5 Sodium citrate 0.25

Distilled water, q.s. ad. 100 ml.

MANUFACTURING INSTRUCTIONS (1) Dissolve the polyethylene sorbitan 60 in water; hydrate the methylcellulose.

(2) Wet the propargylamine 3-hydroxy-2-naphthoate with the polyethylene sorbitan solution and add to the hydrated methylcellulose solution.

(3) Add the sodium saccharin, sodium sucaryl, sugar, sodium benzoate, sodium citrate, dye and flavor.

(4) Bring up to volume with distilled water and homogenize the supension. Each 5 ml. aliquot of the resulting suspension contains 50 mg. of propargyl'amine 3- hydroxy-Z-naphthoate.

An alternative formulation containing a different, and also less readily water-soluble, salt of propargylamine is the following:

Propargylamine salt with one formula Weight of Flavor, q.s. Distilled water, q.s. to 100 ml.

MANUFACTURING INSTRUCTIONS (1) Hydrate the clay; add the sodium benzoate.

(2) Dissolve the polysorbate in water, wet the propargylamine salt with the solution, and the resulting mixture with 1.

(3) Mix the sugar and sodium carboxymethylcellulose. Add slowly to 2. Mix until dissolved.

(4) Add the citric acid and sorbitan.

(5) Add the dye and flavor, and adjust the volume up to cc. with distilled water. Homogenize the suspension. Each 5 ml. aliquot of the resulting suspension contains 10 mg. of propargylamine salt.

I'claim:

A method of combatting depression which comprises administering to a depressed animal a composition in dosage unit form containing as active ingredient an amine compound of the group consisting of propargylamine and physiologically acceptable acid addition salts thereof, the dosage being sufiicient to provide about 10 to 250 mg. of the amine compound calculated as free base per kilogram of body weight per day.

References Cited by the Examiner UNITED STATES PATENTS 3,155,584 11/1964 Martin l67-65 3,221,054 11/1965 Arnold et al 167-65 OTHER REFERENCES Marszak et al. Chemical Abstracts, vol. 50, col. 9279 (i) 1955.

Schluback et al. Chemical Abstracts, vol. 44, col. 8314 (d) 1950.

JULIAN S. LEVITT, Primary Examiner.

LEROY B. RANDALL, Assistant Examiner. 

